It is postulated that tumors arise in a multistep process. This project's objective is to isolate the putative surveillance-susceptible intermediate cell types and determine the class of the immune or nonimmune response (e.g., Ig, CMI, NK, NC) that affects their rejection and how these intermediate cell types might escape immune or nonimmune elimination to grow progressively. We have shown that normal cells (N-cells) can be transformed by chemical carcinogens to intermediate cell types (1-cells); I-cells are tumorigenic yet susceptible to host-protective mechanism so they grow in surveillance-deficient individuals, but do not grow progressively in normal individuals. From these I-cells, variants can be derived which have escaped the host-protective mechanisms (C-cells) so these cells grow progressively in normal individuals. Thus, we have reconstructed the postulated autochthonous pathway from normal to cancerous as predicted by the immune surveillance hypothesis: normal to transformed and surveillance-susceptible to transformed and surveillance resistant (i.e., N to I to C). Using these cell lines we have shown that the N to I step involves the expression, by I-cells, of NC-sensitivity and the expression of antigens associated with transformation that induce antitumor immunity. The I to C step involves escape from both NC activity (i.e., C-cells are NC-resistant) and the immune system. The mechanism by which C-cells escape immunity probably involves "suppression" since C-cells remain as antigenic as the I-cells they are derived from. In addition to analyzing the immune and nonimmune response that mediates the rejection of I-cells and how C-cells escape rejection, we are analyzing the transformed I and C cells to determine the number of different tumor-associated antigens that can be expressed by independent I-cells and the gene-level events required for the N to I step as well as the I to C step. (IB)